Oral compositions for calculus retardation

ABSTRACT

ORAL COMPOSITIONS, SUCH AS TOOTHPASTE, MOUTHWASH, AND THE LIKE, CONTAINING CERTAIN METHANECYCLOALKYLHYDROXYDIPHOSPHONIC ACIDS AND THEIR SALTS WHICH RETARD DENTAL CALCULUS FORMATION WITHOUT DAMAGING THE TOOTH STRUCTURE.

United States Patent O 3,553,314 ORAL COMPOSITIONS FOR CALCULUSRETARDATION Marion D. Francis, Springfield Township, Hamilton County,Ohio, assignor to The Procter & Gamble Company, Cincinnati, Ohio, acorporation of Ohio No Drawing. Filed Dec. 23, 1968, Ser. No. 786,355

Int. Cl. A611 7/16 US. Cl. 42449 8 Claims ABSTRACT OF THE DISCLOSUREOral compositions, such as toothpaste, mouthwash, and the like,containing certain methanecycloalkylhydroxydiphosphonic acids and theirsalts which retard dental calculus formation without damaging the toothstructure.

BACKGROUND OF THE INVENTION The field of this invention is oralcompositions which term is used herein to designate products which inthe ordinary course of usage are retained in the oral cavity for a timesuificient to contact substantially all of the dental surfaces, but arenot intentionally ingested. Such products include, for example,dentifrices, mouthwashes, prophylaxis pastes and topical solutions.

Dental calculus, or tartar as it is sometimes called, is a deposit whichforms on the surface of the teeth at the gingival margin. Supragingivalcalculus appears principally in the areas near the orifices of thesalivary ducts; e.g., on the lingual surfaces of the lower anteriorteeth and on the buccal surfaces of the upper first and second molars,and on the distal surfaces of the posterior molars. Mature calculusconsists of an inorganic portion which is largely calcium phosphatearranged in a hydroxylapatite crystal lattice structure similar to bone,enamel and dentine. An organic portion is also present and consists ofdesquamated epithelial cells, leukocytes, salivary sediment, food debrisand various types of microorganisms.

As the mature calculus develops, it becomes visibly white or yellowishin color unless stained or discolored by some extraneous agency. Inaddition to being unsightly and undesirable from an aestheticstandpoint, the mature calculus deposits are constant sources ofirritation of the gingiva and thereby are a contributing factor togingivitis and other diseases of the supporting structures of the teeth,the irritation decreasing the resistance of tissues to endogenous andexogenous organisms.

A wide variety of chemical and biological agents have been suggested inthe art to retard calculus formation or to remove calculus after it isformed. Mechanical removal of this material periodically by the dentistis, of course, routine dental ofiice procedure.

The chemical approach to calculus inhibition generally involveschelation of calcium ion which prevents the calculus from forming and/orbreaks down mature calculus by removing calcium. A number of chelatingagents have been employed for this purpose. See, for example, BritishPat. 490,384, granted Feb. 15, 1937, which discloses oral compositionscontaining ethylenediaminetetraacetic acid, nitrilotriacetic acid andrelated compounds as anticalculus agents; German Auslegeschrift1,149,138, published May 22, 1963, which discloses certain water-solublediglycolates as anticalculus agents; and US. Pat. 1,516,206 whichdiscloses oral compositions containing various sugar lactones for thispurpose.

Although certain of the art-disclosed chelators are purportedly safe foruse on dental enamel, the chemical similarity of calculus to the toothstructure limits the usefulness of the chelation approach since the moreeffective chelators can seriously damage the tooth structure 3,553,314Patented Jan. 5, 1971 by decalcification. Thus, the development of oralcompositions which effectively retard calculus by calcium chelation hasbeen impeded by safety considerations.

SUMMARY OF THE INVENTION It has now been discovered that certainmethanecycloalkylhydroxydiphosphonic acids and pharmaceuticallyacceptable salts thereof (referred to collectively hereinafter asmethanecycloalkylhydroxydiphosphonates which tennis intended toencompass both the free acid and salt forms) possess the surprisingcapacity to retard the development of dental calculus without removingcalcium from dental enamel or otherwise damaging the tooth structurewhen employed in oral compositions maintained within defined pH limits.

Unlike inorganic polyphosphonates such as pyrophosphates, themethanecycloalkylhydroxydiphosphonates employed in the compositions ofthis invention resist hydrolysis in aqueous products and thereforeremain in an active form throughout the normal shelf-life of suchproducts.

It is, therefore, an object of this invention to provide novel oralcompositions which retard the formation of calculus without otherwiseaffecting the tooth structure.

It is another object of this invention to provide an improved method forretarding the development of dental calculus.

Other objects will become apparent from the following detaileddescription.

DETAILED DESCRIPTION OF THE INVENTION This invention is an oralcomposition effective in inhibiting the formation of dental calculuswithout adversely affecting the tooth structure comprising (1) fromabout .01% to about 10% by weight of amethanecycloalkylhydroxydiphosphonate having the formula:

wherein n is an integer from 3 to 9, or a pharmaceutically acceptablesalt thereof, such as alkali metal (e.g., sodium and potassium),alkaline earth metal (e.g., calcium and magnesium), non-toxic heavymetal (e.g. stannous and indium), ammonium or low molecular weightsubstituted ammonium (e.g., mono-, diand triethanolammonium) salts; and(2) a carrier suitable for use in the oral cavity, the pH of saidcomposition being in the range from about 5.0 to 11.0.

The methanecycloalkylhydroxydiphosphonates can be prepared by methodsfully described in the US. patent application of John D. Curry, entitledNovel Methanecycloalkylhydroxydiphosphonic Acids and Salts Thereof, Ser.No. 786,358, filed Dec. 23, 1968, which is incorporated herein byreference.

S p e c i f i c methanecycloalkylhydroxydiphosphonates which areencompassed by the above general formula and which are useful in thepresent invention include the following:

I Methanecyclooctylhydroxydiphosphonic acidMethanecyclononylhydroxydiphosphonic acidMethanecyclodecylhydroxydiphosphonic acid Each of the sodium, potassium,calcium, magnesium, stannous, indium, ammonium, monoethanolammonium,diethanolammonium and triethanolammonium salts of the above recitedmethanecycloalkylhydroxydiphosphonic acids as well as any otherpharmaceutically acceptable salt of these acids, can be used in thepractice of the present invention.

Especially preferred methanecycloalkylhydroxydiphosphonates for thepurpose of this invention are methanecyclopentylhydroxydisphosphonicacid, methanecycloheptylhydroxydiphosphonic acid and thepharmaceutically acceptable salts of these acids.

The concentration of methanecycloalkylhydroxydiphosphonate in the oralcompositions of this invention can range from about .01% to about 10% byweight. Oral compositions which in the ordinary course of usage could heaccidentally ingested should contain lower concentrations ofmethanecycloalkylhydroxydiphosphonate. Thus, a mouthwash in accordancewith this invention preferably contains less than about 3% by weight ofmethanecycloalkylhydroxydiphosphonate. Dentifrice compositions, topicalsolutions and prophylaxis pastes, the latter to be administeredprofessionally can contain up to about 10% by weight, preferably fromabout 0.1% to about 5.0% by weight ofmethanecycloalkylhydroxydiphosphonate.

The pH of the composition of this invention can range from about 5.0 toabout 11. Below about pH 5.0 damage to the dental enamel can occur inspite of the relative safety of themethanecycloalkylhydroxydiphosphonates. Above about pH 11.0 difficultyis encountered in formulating products having satisfactory flavor andmildness. A preferred pH range is from about 7.0 to about 10. The pH ofthe composition, of course, is determinative of the predominant saltform of the methanecycloalkylhydroxydiphosphonates present therein.

While it is not intended that this invention be limited by a particulartheory of operation, it has been observed that the methanecycloalkylhydroxydiphosphonates encompassed herein interfere with the progress ofcalculus formation by interfering with the conversion of amorphouscalcium phosphate to crystalline calcium hydroxyl apatite. Amounts ofmethanecycloalkylhydroxydiphosphonates which are much too small tochelate any appreciable quantities of calcium have been found to retardthe formation of calcium hydroxylapatite. This selective action on theformative calculus deposits without demineralizing action on the dentalenamel is surprising.

The eflicacy of the compositions of this invention in calculusprophylaxis is demonstrated by the rat calculus and crystal growthinhibition tests which are conducted as follows:

RAT CALCULUS TEST Two groups of 20 to 21-day old Holtzman-Sprague-Dawley strain rats, each group comprising one male and one female memberof each of 10 litters, were employed in this test, one group serving asthe control and the other serving as the test group. The control groupof animals was placed on a calculus inducing diet consisting of 50%cornstarch, 32% non-fat dry milk, 3% liver powder, celluflour, 1%cottonseed oil, 5% powdered sucrose, 1% CaCl -2H O, 2.7% NaH PO' -H Oand 0.3% MgSO The test group of animals was placed on an identical dietexcept that 0.25% of methanecyclohexylhydroxydiphosphonate was addedthereto.

Three weeks after the commencement of the test, the animals weresacrificed and their molars were graded for severity of calculus byassessing the area and depth of accumulation on each of the 44 dentalsurfaces examined in each animal. Grading was made on a 0-3 scale foreach surface, 0 being no detectable calcified deposits, 3 being coverageof 50100% of the surface with a thick deposit and intermediate valuesrepresenting gradations between these extremes. The total calculus scorefor each animal was determined by adding the grades for each of the 44surfaces.

The average of total calculus scores was 78.83 in the control group and1.30 in the test group representing a 98.4% reduction in calculus.

CRYSTAL GROWTH INHIBITION DETERMINATION As hereinbefore stated, themethanecycloalkylhydroxydiphosphonates inhibit the growth of calciumhydroxylapatite crystals and in this way interfere with the normalformation of calcium hydroxylapatite from solution. This test is todetermine the effects of the methanecycloalkylhydroxydiphosphonates onthe calcium phosphonate formed on addition of calcium ion toorthophosphate ion at constant pH. The procedure is as follows:

1 ml. of a 0.1 M stock solution of NaH PO -H O is diluted with 22 ml. ofdistilled water. 1 ml. of an aqueous solution of themethanecycloalkylhydroxydiphosphonate to be tested (at a concentrationsufficient to provide the desired ultimate concentration in the reactionmixture) is added to the diluted NaH PO solution and the solution isadjusted to pH 7.4 with sodium hydroxide. To this solution is added 1ml. of a 0.1 M solution of CaCl -2H O preadjusted to pH 7.4 with sodiumhydroxide. This mixture is held at a constant pH 7.4 throughout thereaction period.

After a sufiicient reaction time (as determined by the operator),generally within minutes, the solution is filtered through a 0.4511.millipore filter pad. The precipitate is air-dried and analyzed by X-raydiffraction. The solid calcium phosphate precipitated from theabove-described solution without a methanecycloalkylhydroxydiphosphonategives a typical hydroxylapatite pattern, while the calcium phosphateprecipitated under the same conditions but in the presence of smallamounts of the methanecycloalkylhydroxydiphosphonates of this inventionis amorphous to X-rays.

Table 1 below shows the concentration of various polyphosphonates testedrequired to inhibit the formation of calcium hydroxylapatite under theconditions specified above.

TABLE 1 M concentration Compound: for inhibitionMethanecyclopentylhydroxydiphosphonic acid, trisodium salt 5.00 l0Methanecyclohexylhydroxydiphosphonic acid, trisodium salt 5.00 10Methanecycloheptylhydroxydiphosphonic acid, monosodium salt 5.O0 10- Thepresence of the specified amounts of themethanecycloalkylhydroxydiphosphonates of Table 1 in the test solutionsof the crystal growth inhibition test results in the precipitation of anamorphous calcium phosphate rather than crystalline calciumhydroxylapatite as occurs without methanecycloalkylhydroxydiphosphonateand the total formation of calcium orthorphosphate is greatly decreased.By way of comparison, ethylenediaminetetraacetic acid andnitrilotriacetic acid which have been suggested for use as anticalculusagents in the art fail to inhibit crystal growth at molar concentrationsof 2.45 1O- and 2.54 l0 respectively. At higher concentrations, theseprior art compounds prevent precipitation of calcium phosphate in thistest because of their powerful calcium sequestering properties.

A dentifrice, especially toothpaste, containing amethanecycloalkylhydroxydiphosphonate is preferred embodiment of thisinvention. Toothpaste compositions conventionally contain abrasivematerials, sudsing agents, binders, humectants, flavoring and sweeteningagents.

The abrasive materials and other adjuncts used in the practice of thisinvention are preferably not sources of much soluble calcium so that thecrystal growth inhibiting capacity ofmethanecycloalkylhydroxydiphosphonate is not depleted to an extent thatits anticalculus activity is impaired. Thus, conventional abrasives suchas dicalcium orthophosphate and calcium carbonate are preferably notused. However, predominantly B-phase calcium pyrophosphate prepared inaccordance with the teachings of Schweizer, US. Pat. 3,112,247, grantedNov. 26, 1963, which contains relatively little soluble calcium can beused. An especially preferred class of abrasives for use herein are theparticulate thermosetting polymerized resins as described by Cooley etal. in US. Pat. 3,070,510, granted Dec. 25, 1962. Suitable resinsinclude, for example, melamines, phenolics, ureas, melamine-ureas,melamine formaldehydes, urea formaldehydes, melamine urea formaldehydes,cross linked epoxides, and cross-linked polyesters.

Other suitable abrasives include alumina and the insoluble non-calciummetaphosphates such as sodium metaphosphate. Mixtures of abrasives canalso be used. In any case, the total amount of abrasive in thedentifrice embodiments of this invention can range from 0.5% to 95% byweight of the dentifrice. Preferably, toothpastes contain from 20% to60% by weight of abrasive. Abrasive particle size preferably ranges from2,3 to 20 Suitable sudsing agents are those which are reasonably stableand form suds throughout a wide pH range, preferably non-soap anionicorganic synthetic detergents. Examples of such agents are water-solublesalts of alkyl sulfate having from to 18 carbon atoms in the alkylradical, such as sodium lauryl sulfate; water-soluble salts ofsulfonated monoglycerides of fatty acids having from 10 to 18 carbonatoms, such as sodium monoglyceride sulfonates; salts of C -C fatty acidamides of taurine, such as sodium N-methyl-N-palmitoyl tauride; salts ofC C fatty acid esters of isethionic acid; and substantially saturatedaliphatic acyl amides of saturated monoaminocarboxylic acids having 2 to6 carbon atoms and in which the acyl radical contains 12 to 16 carbonatoms, such as sodium N-lauroyl sarcoside. Mixtures of two or moresudsing agents can be used.

The sudsing agent can be present in the dentifrice compositions of thisinvention in an amount from 0.5% to 5% by weight of the totalcompositions.

In preparing toothpastes, it is necessary to add some thickeningmaterial to provide a desirable consistency. Preferred thickening agentsare hydroxyethyl cellulose and water-soluble salts of cellulose etherssuch as sodium carboxymethyl cellulose and sodium carboxymethylhydroxyethyl cellulose. Natural gums such as gum karaya, gum arabic, andgum tragacanth can also be used. Colloidal magnesium aluminum silicateor finely divided silica can be used as part of the thickening agent tofurther improve texture. Thickening agents in an amount from 0.5% to5.0% by weight of the total composition can be used.

It is also desirable to include some humectant material in a toothpasteto keep it from hardening. Suitable humectants include glycerine,sorbitol, and other edible polyhydric alcohols. The humectant cancomprise up to about 36% by weight of the toothpaste composition.

Suitable flavoring agents include oil of Wintergreen, oil of peppermint,oil of Spearmint, oil of Sassafras, and oil of clove. Sv'veeteningagents which can be used include saccharin, dextrose, levulose andsodium cyclamate.

Several representative oral compositions illustrating this invention areset forth in the following examples.

EXAMPLE I A toothpaste of the following composition is prepared byconventional methods:

Sodium coconut monoglyceride sulfonate Sodium carboxymethyl cellulose1.15

EXAMPLE I.-Continued Parts by weight Magnesium aluminum silicates 0.40Flavoring 0.85 Trisodium salt of methanecyclohexylhydroxydiphosphonicacid pH, 5.90.

1 Prepared Nov. 26, 1963 This composition effectively retards calculusformation Without damaging dental enamel.

Toothpaste compositions substantially identical to the composition ofExample I are prepared with methanecyclobutylhydroxydiphosphonic acid;methanecyclopentylhydroxydiphosphonic acid,methanecycloheptylhydroxydiphosphonic acid,methanecyclooctylhydroxydiphosphonic acid,methanecyclononylhydroxydiphosphonic acid, andmethanecyclodecylhydroxydiphosphonic acid, respectively, rather than thetrisodium salt of methanecyclohexylhydroxydiphosphonic acid, adjustingthe pH to 5.9. These compositions substantially retard calculusformation and do not decalify dental enamel.

EXAMPLE II Yet another toothpaste is prepared having the followingcomposition:

in accordance with U.S. Pat. 3,112,247 granted When employed in thecustomary manner, this toothpaste retards the formation of dentalcalculus and no decalcification of dental enamel is observed.

Several additional toothpastes are prepared having essentially the samecomposition as the toothpaste of Example II, but using the tripotassiumsalt of methanecyclopentylhydroxydiphosphonic acid; the monoammoniumsalt of methanecyclohexylhydroxydiphosphonic acid; the

'monocalcium salt of methanecyclooctylhydroxydiphosphonic acid; thedimagnesium salt of methanecyclodecylhydroxydiphosphonic acid; thedistannous salt of methanecyclohexylhydroxydiphosphonic acid; and themonoindium salt of methanecyclopentyldroxydiphosphonic acid,respectively, rather than the monosodium salt ofmethanecycloheptylhydroxydiphosphonic acid. The pH of these compositionsis adjusted to 7.0. These toothpaste formulations effectively retardcalculus formation on dental enamel Without decalcifying same.

Several mouthwash compositions are prepared in accordance with thisinvention as follows:

Example (parts by weight) III IV V VI 1 Polyoxyethylene (20 moles ofethylene oxide) sorbitan mono-oleate, a

Component Glycerine. ol

Tween Saccharin Sodium oyclamate vorMethanecycloalkylhydroxydiphosphonate nonionic emulsifier supplied byAtlas Powder Company.

2 Monosodium salt of methanecycloheptylhydroxydiphosphonic acid. 3Trisodium salt of methanecyclohexylhydroxydiphosphonic acid.

4 Trisodium salt of methanecyclopentylhydroxydiphosphonic acid.

6 Trisodium salt; of methanecyclooctylhydroxydiphosphonic acid.

6 Adjusted to value indicated with sodium hydroxide.

7 When used in the same manner as conventional mouthwash, at least oncedaily, each of the above compositions materially reduces accumulation ofcalculus on the surfaces of teeth. No decalcification of dental enamelis observed after several days exposure.

EXAMPLE VII A prophylaxis paste for use by the dentist for removal ofstains and polishing the teeth after mechanical removal of calculusdeposits is formulated as follows:

Parts by weight Bis(triethanolammonium) salt ofmethanecyclohexylhydroxydiphosphonic acid pH, 8.0.

When applied to the teeth with a prophylactic rubber cup in theconventional manner, this composition retards the development of newcalculus deposits.

The prophylaxis paste set forth above is modified by replacing thebis(diethanolammonium) salt of methanecyclohexylhydroxydiphosphonic acidwith the bis(diethanolarnmonium) salt ofmethanecyclopentylhydroxydiphosphonic acid, and thebis(monoethanolammonium) salt of methanecycloheptylhydroxydiphosphonicacid, respectively, with comparable results.

Toothpowders and the like can be prepared by conventional methods andcontaining, in addition to the usual ingredients, an amount ofmethanecycloalkylhydroxydiphosphonate within the ranges specifiedherein, to provide an effective means of retarding calculus formationWithout damaging the tooth structure.

Those components other than methanecycloalkylhydroxydiphosphonates whichwere included in the foregoing examples and various mixtures of thosecomponents are illustrative of carriers suitable for use in the oralcavity.

In the reference to pH adjustments in the foregoing examples, it is tobe understood that a base of a cation corresponding to the salt form ofthe methanecycloalkylhydroxydiphosphonate employed is used to adjust tohigher pH values. In each case in which themethanecycloalkylhydroxydiphosphonate was added in its acid form to theexample compositions, the pH was adjusted to the specified higher valuewith NaOH. Adjustments in pH to more acid levels is accomplished withHCl acid. It will be obvious to those skilled in the art that pHadjustments can be made with any acid or base suitable for use in theoral cavity.

What is claimed is:

1. An oral composition effective in inhibiting the formation of dentalcalculus without adversely affecting tooth structure, comprising (1)from about .01% to about 10% by weight of amethanecycloalkylhydroxydiphosphonate of the formula:

wherein n is an integer of from 3 to 9, or a pharmaceutically acceptablesalt thereof; and (2) a carrier suitable for use in the oral cavity, thepH of the composition being within the range from about 5.0 to about11.0.

2. The composition of claim 1 in which themethanecycloalkylhydroxydiphosphonate ismethanecyclopentylhydroxydiphosphonic acid or a pharmaceuticallyacceptable salt thereof.

3. The composition of claim 1 in which themethanecycloalkylhydroxydiphosphonate ismethanecyclohexylhydroxydiphosphonic acid or a pharmaceuticallyacceptable salt thereof.

4. The composition of claim 1 in which themethanecycloalkylhydroxydiphosphonate ismethanecycloheptylhydroxydiphosphonic acid or a pharmaceuticallyacceptable salt thereof.

5. A toothpaste composition comprising (1) from about .01% to about 10%by weight of a methanecycloalkylhydroxydiphosphonate of the formula:

wherein n is an integer of from 3 to 9, or a pharmaceutically acceptablesalt thereof; and (2) a carrier suitable for use in the oral cavity, thepH of the composition being within the range from about 5.0 to about11.0.

6. The composition of claim 5 in which themethanecycloalkylhydroxydiphosphonate ismethanecyclopentylhydroxydiphosphonic acid or a pharmaceuticallyacceptable salt thereof.

7. The composition of claim 5 in which themethanecycloalkylhydroxydiphosphonate ismethanecyclohexylhydroxydiphosphonic acid or a pharmaceuticallyacceptable salt thereof.

8. The composition of claim 5 in which themethanecycloalkylhydroxydiphosphonate ismethanecycloheptylhydroxydiphosphonic acid or a pharmaceuticallyacceptable salt thereof.

References Cited Dental Abstracts, vol. 12, No. 9, pp. 539-544,September 1967.

Draus et al.: Dental Progress, vol. 3, No. 2, pp. 79-81, January 1963.

Grossman: J. Oral Surg., Oral Med., and Oral Path., vol. 7, pp. 484-487,May 1954.

RICHARD L. HUFF, Primary Examiner U.S. Cl. X.R. 260502.4

